Akt proteins are serine-threonine protein kinases characterized by activation of phosphorylation at two sites (Thr308 and Ser473) through a phosphatidylinositol 3-kinase (PI3K)-dependent process. Specifically, Akt proteins refer to growth factor signals and other stimuli that activate PI3K and promote accumulation of D3-phosphorylated phosphoinositides at the plasma membrane. The interaction of these phosphoinositides with the pleckstrin homology (PH) domain of Akt promotes the translocation of the kinase to the plasma membrane, for phosphorylation by PI3K-dependent kinase-1 (PDK1) at Thr308 and by mTOR (mammalian target of rapamycin) complex-2 (TORC2) at Ser473 (Bellacosa et al., 1991 Science 254: 274-277; Franke et al., 1995 Cell 81: 727-736; Manning et al., 2007 Cell 129: 1261-1274).
Akt is linked with the induction and progression of human cancer (Altomare et al., 2005 Oncogene 24: 7455-7464). However, there are three Ala isoforms and information regarding their specific oncogenic activities is limited. The Akt1 and Akt2 isoforms appear to play different roles in mammary adenocarcinomas induced in mice by transgenes encoding the oncoproteins polyoma middle T and ErbB2 (also known as Neu), both of which activate the PI3K-Akt pathway. Ablation of Akt1 inhibits—whereas ablation of Akt2 accelerates—tumor induction and growth by both polyoma middle T and ErbB2 (Maroulakou et al., 2007 Cancer Res. 67: 167-177; Ju et al., 2007 Proc. Natl. Acad. Sci. U.S.A. 104: 7438-7443). However, the tumors developing in the Akt1 knockout mice are more invasive than the tumors developing in Akt2 knockout and wild-type mice (Maroulakou et al., 2007 Cancer Res. 67: 167-177). Ablation of Akt1 may also enhance tumor invasiveness, a process separate from and independent of tumor induction and growth (Chiang et al., 2008 N. Engl. J. Med. 359: 2814-2823). These findings were consistent with observations showing that Akt1 knockdown promotes migration and invasiveness of human mammary epithelial cells in culture (Irie et al., 2005 J. Cell Biol. 171:1023-1034; Yoeli-Lerner et al., 2005 Mol. Cell 20: 539-550; Liu et al., 2006 Proc. Natl. Acad. Sci. U.S.A. 103: 4134-4139), perhaps by promoting epithelial-mesenchymal transition (EMT), a process that plays important roles in both development and oncogenesis. During EMT, epithelial cells acquire a mesenchymal phenotype characterized by the loss of intercellular junctions and increased cell migration. On the molecular level, cells undergoing EMT decrease the abundance of epithelial cell-specific proteins, such as E-cadherin, and increase the abundance of mesenchymal cell-specific proteins, such as vimentin. The developmental switch characteristic of EMT renders tumor cells undergoing this process more invasive and metastatic. Thus, inhibition of individual Akt isoforms may have both desirable and undesirable effects during oncogenesis.
MicroRNAs are a class of molecules that regulate gene expression by various mechanisms and play important roles in oncogenesis (Calin et al., 2005 Proc. Natl. Acad. Sci. U.S.A. 101: 11755-11760; Lu et al., 2005 Nature 435: 834-838). Like conventional oncogenes and tumor suppressor genes, microRNAs may either promote or inhibit oncogenesis. Also, like conventional cancer genes, their expression is selectively increased or decreased in various human and animal tumors. The selective deregulation of microRNA gene expression may be due to deletions, amplifications, or mutations targeting the microRNAs themselves or their regulatory sequences, as well as to dysregulation of transcription factors and epigenetic regulators targeting the genes encoding them (Croce, 2009 Nat. Rev. Genet. 10: 704-714). Understanding the regulation and functional activities of individual microRNA families in cancer and other human diseases could thus lead to new opportunities for therapeutic intervention.
Cancer remains a major public health problem among adults, and is the leading disease-related cause of death in children. Therapeutic agents in use are limited by substantial side effects, including chemotherapeutic agents that cause fatigue and nausea, and radiation with other iatrogenic effects. There remains a need for novel methods of detecting and novel compositions and methods for treating cancers, and for early stage prognosis of cancer.